What is important with these drugs, specifically with tepotinib, capmatinib, and even newer agents that are being tested like savolitinib, is that these agents have meaningful activity and are well tolerated. Most of the toxicities that we saw in the VISION and Geometry Mono-1 trials were grade 1 and 2. That’s important. The most common adverse events we see with these agents include edema and GI [gastrointestinal] toxicities—potentially nausea and constipation. We sometimes see an increase in liver function tests [LFTs] with these drugs. But overall, both are reasonably well tolerated, at least in my experience. We need to watch out for the nausea. The most common events seen with these drugs are peripheral edema and nausea, but there are ways to manage both. Keeping patients mobile can help with the peripheral edema. Regarding nausea, this is not an uncommon adverse effect we see with other types of treatments, including chemotherapy, so we’re all familiar with managing nausea with certain oral agents. In terms of liver function abnormalities, this is something that we have to sometimes do a watch-and-wait approach. Sometimes we have to take patients off the drug for a bit to see that their LFT is correct. But most times, we can do a dose decrement rather than take the patient off therapy completely. This where medicine becomes an art and not a science. Fortunately, we’re not forced to mitigate that much toxicity with measures that we have to institute in our clinic. Overall, the drugs are reasonably well tolerated. It’s not to say they’re perfect, so we just have to be mindful of these toxicities, including, again, peripheral edema, nausea, fatigue, and LFT abnormalities.

The primary adverse event I worry about when I’m starting a patient on either capmatinib or tepotinib is peripheral edema. This is a real issue. We see leg swelling that can effect quality of life. I have found that dose reductions can lead to improved outcomes. Sometimes, we do have to hold the drug. The edema that we’re talking about is not terribly responsive, in my experience, to diuretics, so I tend to work with dose reductions and dose holds. I get nervous about dose holds given the high dependency of these tumors for MET signaling, so I tend to utilize more dose reductions than dose holds.

Videos

Drs Joshua M. Bauml and Benjamin Levy highlight more common adverse events associated with MET inhibitors used to treat MET exon 14 skipping mutations in non–small cell lung cancer and share strategies to help manage patients on therapy.

MET Inhibitors in NSCLC: Toxicity Management 

Capmatinib and tepotinib are both MET tyrosine kinase inhibitors. They work by interrupting the signal through the activated MET receptor. There are 2 types of MET inhibitors—type 1 and type 2—and the distinction between each type is based on where the MET tyrosine kinase inhibitor binds to. Examples of type 1 tyrosine kinase inhibitors are crizotinib, capmatinib, tepotinib, savolitinib. Examples of type 2 MET inhibitors are cabozantinib and glesatinib. We think there could be potential for using a type 2 MET inhibitor after a type 1 MET inhibitor for some patients who develop resistance to type 1 MET inhibitors in the binding site of a MET tyrosine kinase inhibitor.

There are different types of MET-directed therapies. The most common ones, or the ones that are approved, are the type 1 inhibitors capmatinib and tepotinib. These drugs work fairly similarly in terms of their mechanisms of action. That’s why we’re seeing some similarities in the data in terms of response rates. There may be a few differences in terms of their adverse effects, but overall, these drugs are designed and work very similarly at the level of the tumor.

There are other MET-directed therapies. Type 2 MET-directed therapies include cabozantinib. These drugs may be better suited to overcome MET resistance with secondary mutations. But overall, the take-home point here is these drugs are relatively similar in their efficacy, mechanisms of action, and adverse effects. There are not big differences. There may be a few differences in toxicity between savolitinib and capmatinib and tepotinib, but overall, these drugs are relatively the same.

Both capmatinib and tepotinib have excellent efficacy, as well as pretty similar adverse-effect profiles. The big things that differentiate them are how they are dosed. Capmatinib is given 2 times a day, while tepotinib is given once a day. That’s pretty much it. I will say that I have more experience utilizing capmatinib, so I tend to use that as my first choice. However, if a patient’s insurance would only provide for tepotinib, I would have no concerns about giving them that. I will note that in the trial of capmatinib as first-line therapy, capmatinib had a much higher response rate compared with tepotinib in the first line. I’m not sure if that’s a statistical fluke or something real. We’ll have to follow these patients and figure this out.

A comparison between the MET inhibitors available to treat MET exon 14 skipping mutations in non–small cell lung cancer and factors that should be considered when selecting a type 1 or type 2 MET-directed therapy. 

MET Inhibitors in NSCLC: Treatment Selection

 alterations in lung cancer is a long one. We have looked at multiple drugs targeting MET, recognizing that MET is a critical part of the signaling cascade in lung cancer. There have been monoclonal antibodies targeting this, but we have really struggled to figure out what the real predictive biomarker is here, whether it’s circulating biomarkers, whether it is immunohistochemistry for MET. But in the process of learning about this, 

 exon 14 skipping alterations were identified. These are splice site variants that lead to loss of exon 14. We have learned that such patients responded quite well to MET-based therapies. Historically, we had crizotinib, which was a PAN inhibitor but did have MET activity. Some efficacy was demonstrated with the use of that drug. But capmatinib and tepotinib, the 2 recently approved MET inhibitors, have much higher affinity for MET and have led to very nice response rates.

We’ve come a long way in regard to the therapeutic options for patients with 

 exon 14 skipping mutations in lung cancer. This is a relevant genetic alteration in lung cancer. It makes up anywhere from 2% to 4% of all lung cancer cases. We’ve made significant advances here.

The first drug that we started exploring in this molecular niche was crizotinib. Crizotinib data looked fairly promising. In highly pretreated groups of patients with 

 exon 14 skipping mutations, we’ve seen that crizotinib elicits response rates anywhere from 30% to 35%. The PFS [progression-free survival] is around 7 to 8 months.

Now we have 2 new approvals for targeted therapies that selectively inhibit tumors that harbor 

 exon 14 skipping mutations. The first is capmatinib. This is an oral therapy. We’ve now got data generated that show that this drug elicits meaningful responses for patients with lung cancer with 

 exon 14 skipping mutations. We’ve seen response rates in previously untreated patients of close to 70%, and we’ve seen response rates in previously treated patients to be around 40%.

The second approval is for tepotinib, another MET-directed therapy recently approved. Again, in patients with lung cancer harboring 

 exon 14 skipping mutations, for treatment-naive patients we’ve seen roughly 45% response rates. In previously treated patients, we’ve seen a 45% response rate. So I think overall, we’ve made significant advances. We’ve come a long way. Crizotinib, of course, was the first, but we have 2 new drug approvals—capmatinib and tepotinib—that are exciting to use and are big wins for our patients as we try to advance the field.

Drs Joshua M. Bauml and Benjamin Levy react to the development of novel therapies that specifically target MET exon 14 skipping mutations in non–small cell lung cancer.

Advances in Targeting MET Exon 14 Skipping Mutations in NSCLC

MET is a tyrosine kinase receptor. Usually, hepatocyte growth factor is a ligand for MET. Once MET has been activated, it results in dimerization and signaling through multiple intracellular pathways, resulting in tumor growth and proliferation. What’s interesting is how 

 exon 14 skipping mutations affect MET signaling. Usually, a mutation resulting in the skipping of exon 14 happens in the intron region of MET, resulting in alternative splicing, and therefore, deletion of the juxtamembrane domain of the MET receptor. The juxtamembrane domain is very important because that’s where Cbl binds, and Cbl marks the receptor for degradation. So, there is no place for Cbl to bind. The receptor does not get degraded. Therefore, it continues to signal, resulting in tumor growth.

exon 14 skipping mutations range from about 1.5% to 6%, depending on what data you are reading. The largest data set reported was by Garrett Frampton, PhD, which looked at 38,000 patients who received sequencing by the Foundation Medicine, Inc platform. They found the incidence of 

 exon 14 skipping mutations to be approximately 3%.

It is also interesting that a very rare subtype of lung cancer called sarcomatoid carcinoma has been reported to have a higher incidence of 

 exon 14 skipping mutations. Xue-wen Liu, MD, PhD, reported that 22% of patients with sarcomatoid carcinoma have 

 exon 14 skipping mutations can be found in both adenocarcinoma and squamous cell carcinoma. Patients with adenocarcinoma are more likely to harbor 

 exon 14 skipping mutations. The majority of those patients are nonsmokers, but smokers have also been described to have 

Another thing we have not touched upon yet is 

 exon 14 skipping mutations, and they happen in approximately 1% of patients. 

is also felt to be an oncogenic driver, because patients with 

 exon 14 skipping mutations are less likely to have other concurrent genomic alterations.

 exon 14 skipping alterations tend to occur about 5% of the time in nonsquamous non–small cell lung cancer, though they can occur at higher rates in certain histologies. Most notably, the rates are as high as 20% in sarcomatoid non–small cell lung cancer. So, it’s critical that we get testing done. One of the important things to remember when you’re doing this testing is that the mutation is in the intron of 

. And so, if your next-generation sequencing panel tends to focus on the exons, it will miss this. I know that many of my colleagues who are utilizing DNA-based next-generation sequencing may miss detecting 

 exon 14 skipping alterations. In fact, using our next-generation sequencing assay at the University of Pennsylvania, I have found most of our alterations detected are on our RNA-based fusion assay as a 13-to-15 fusion, which is another way of saying exon 14 was skipped.

In terms of the risk factors, as I mentioned, patients with sarcomatoid lung cancer are at the highest risk. However, this is an alteration that can be found in people with a smoking history. They tend to be older than your other molecular driver alteration patient populations. Those are the major risk factors.

Drs Joshua M. Bauml and Lyudmila A. Bazhenova describe what is understood regarding the behavior of MET exon 14 skipping mutations in non–small cell lung cancer and remark on their prevalence among specific patient populations.

Joshua M. Bauml, MD, Perelman School of Medicine, University of Pennsylvania

Articles

MET Inhibitors in NSCLC: Toxicity Management

MET Inhibitors in NSCLC: Treatment Selection

Advances in Targeting MET Exon 14 Skipping Mutations in NSCLC

MET Exon 14 Skipping Mutations in NSCLC